Eicosanoids
Eicosanoids are bioactive signaling lipids generated from arachidonic
acid and related polyunsaturated fatty acids (PUFAs) that govern a wide
range of homeostatic and inflammatory processes associated with a
variety of illnesses (Dennis & Norris, 2015). One of the most
well-known routes involved in inflammation is the eicosanoid pathway.
Inflammatory processes are the body’s physiological response to numerous
stressors such as trauma, infections, or immunological reactions. These
processes are distinguished by the activation of cellular and humoral
mediator systems, as well as the production of a wide range of
inflammatory mediators such as interleukin-1 (IL-1) and tumor necrosis
factor-alpha (TNF-α). Increased amounts of these mediators can cause
changes in microvascular tone and permeability, as well as activation of
eicosanoid production pathways (Homaidan, Chakroun, Haidar & El-Sabban,
2002). The availability of free AA is critical for eicosanoid
production. When tissues are exposed to physiological or pathological
stimuli such as growth factors, hormones, or cytokines, AA is generated
from membrane phospholipids by the action of phospholipase A2 (PLA2)
enzymes and can then be converted into different eicosanoids. The three
principal enzymes capable of metabolizing AA are P-450 epoxygenase,
cyclooxygenases (COXs), and lipoxygenases (LOXs) (Harizi, Corcuff &
Gualde, 2008). Following PLA2 cleavage, the freed AA is processed by
three different mechanisms: cyclooxygenase (COX), lipoxygenase (LOX),
and the P450 family (CYP). The COX system produces prostaglandins (PG)
and thromboxanes (TX), while the LOX system produces leukotrienes (LT),
hydroxyeicosatetraenoic acids (HETE), and lipoxins (LX). Finally, the
CYP pathway produces epoxyeicosatrienoic acids (EET) and
heterecosatrienoic acids (HETE). Although free arachidonic acid is
required for the majority of eicosanoid metabolism, it is typically kept
in esterified form. Phospholipase A2 (PLA2) enzymes are essential for
boosting free arachidonic acid levels for metabolism and eicosanoid
production under normal physiological settings, but especially after
inflammatory cell activation. PLA2 isoforms comprise various cystosolic,
calcium dependent, and secretory isoforms, in addition to phospholipases
A1, B, C, and D. Phospholipase activity can be influenced by calcium,
phosphorylation, and agonists that bind to G-protein coupled receptors.
These enzymes are generally involved in the physiological remodeling of
cellular membranes, with free fatty acids being extracted via
phospholipase activity and subsequently recycled with another free fatty
acid. Nonetheless, decreases in the cell’s ability to sustain normal
metabolic function, as well as the resulting drop in ATP levels, might
result in the failure to recycle membrane phospholipids. Modification of
membrane phospholipids is likely to affect a variety of cellular
processes, including the capacity to accumulate excitotoxic amino acids.
It was discovered in this study that selective phospholipase inhibitors
limit the release of free fatty acids from in vivo rat brain. Following
this inhibition, the severity of cortical damage after focal ischemia,
forebrain ischemia, and cerebral trauma is reduced. Infarct volumes were
similarly shown to be smaller in mice with PLA2 deletion (Phillis &
O’Regan, 2003). Further research is needed to completely understand the
role of Eicosanoids in events following SAH.